Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins
Abstract Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analy...
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| Format: | Article |
| Language: | English |
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BMC
2019-12-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-019-0124-z |
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| author | Lourdes Valdés-Sánchez Sofia M. Calado Berta de la Cerda Ana Aramburu Ana Belén García-Delgado Simone Massalini Adoración Montero-Sánchez Vaibhav Bhatia Eduardo Rodríguez-Bocanegra Andrea Diez-Lloret Daniel Rodríguez-Martínez Christina Chakarova Shom S. Bhattacharya Francisco J. Díaz-Corrales |
| author_facet | Lourdes Valdés-Sánchez Sofia M. Calado Berta de la Cerda Ana Aramburu Ana Belén García-Delgado Simone Massalini Adoración Montero-Sánchez Vaibhav Bhatia Eduardo Rodríguez-Bocanegra Andrea Diez-Lloret Daniel Rodríguez-Martínez Christina Chakarova Shom S. Bhattacharya Francisco J. Díaz-Corrales |
| author_sort | Lourdes Valdés-Sánchez |
| collection | DOAJ |
| description | Abstract Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations. |
| first_indexed | 2024-12-21T12:11:50Z |
| format | Article |
| id | doaj.art-4203642594924275af0ef4649cdbe192 |
| institution | Directory Open Access Journal |
| issn | 1076-1551 1528-3658 |
| language | English |
| last_indexed | 2024-12-21T12:11:50Z |
| publishDate | 2019-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-4203642594924275af0ef4649cdbe1922022-12-21T19:04:33ZengBMCMolecular Medicine1076-15511528-36582019-12-0126112210.1186/s10020-019-0124-zRetinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteinsLourdes Valdés-Sánchez0Sofia M. Calado1Berta de la Cerda2Ana Aramburu3Ana Belén García-Delgado4Simone Massalini5Adoración Montero-Sánchez6Vaibhav Bhatia7Eduardo Rodríguez-Bocanegra8Andrea Diez-Lloret9Daniel Rodríguez-Martínez10Christina Chakarova11Shom S. Bhattacharya12Francisco J. Díaz-Corrales13Regeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideInstitute of Ophthalmology, University College LondonInstitute of Ophthalmology, University College LondonRegeneration and Cell Therapy Department, Andalusian Molecular Biology and Regenerative Medicine Centre-CABIMER (Junta de Andalucía), CSIC, Universidad de Sevilla, Universidad Pablo de OlavideAbstract Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.https://doi.org/10.1186/s10020-019-0124-zHSP70PRPF31Retinal degenerationRetinal pigment epitheliumRetinitis pigmentosa |
| spellingShingle | Lourdes Valdés-Sánchez Sofia M. Calado Berta de la Cerda Ana Aramburu Ana Belén García-Delgado Simone Massalini Adoración Montero-Sánchez Vaibhav Bhatia Eduardo Rodríguez-Bocanegra Andrea Diez-Lloret Daniel Rodríguez-Martínez Christina Chakarova Shom S. Bhattacharya Francisco J. Díaz-Corrales Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins Molecular Medicine HSP70 PRPF31 Retinal degeneration Retinal pigment epithelium Retinitis pigmentosa |
| title | Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
| title_full | Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
| title_fullStr | Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
| title_full_unstemmed | Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
| title_short | Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
| title_sort | retinal pigment epithelium degeneration caused by aggregation of prpf31 and the role of hsp70 family of proteins |
| topic | HSP70 PRPF31 Retinal degeneration Retinal pigment epithelium Retinitis pigmentosa |
| url | https://doi.org/10.1186/s10020-019-0124-z |
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